Proper control of gene expression underlies the function of all cells. Regulation of translation is one form of control. Translational control factors bind to cis-acting regulatory elements within mRNAs and, by a variety of mechanisms, repress or activate their translation. Disruption of translational control can be very damaging. For example, mutation of the Fragile X mental retardation protein, which binds specifically to mRNAs and regulates their translation, has devastating consequences in humans. It is generally accepted that a cis-acting translational control element can act only on the mRNA in which it resides. However, we recently found that these elements can act in trans. Regulation in trans very likely depends on physical association of the two types of participating transcripts: those that provide regulatory information, and those that receive regulatory information. Concentration of mRNAs in particles is widespread. All mRNAs are associated with proteins in messenger ribonucleoprotein complexes (mRNPs), which are often assembled into larger particles that can be visualized by light microscopy and have the potential to create a high local concentration of mRNAs. These mRNAs exist in a shared microenvironment, and their proximity raises the possibility of interactions between different transcripts, and the potential for trans regulation. The goals of this project are (i) to better characterize the known example of trans regulation, (ii) to determine which forms of translational control are susceptible to regulation in trans, and (iii) to test additional mRNAs for regulation in trans. Progress should reveal if trans regulation is relatively common but not previously detected because of limitations of the methods and reagents commonly used to study translational control. The broad significance of this work is that the phenomenon of trans regulation, in which one mRNA can influence the activity of other mRNAs, has the potential to explain RNA gain-of-function diseases such as myotonic dystrophy, spinocerebellar ataxia 8, Huntington's disease-like 2 and fragile X-associated tremor ataxia syndrome.

Public Health Relevance

Proper regulation of gene expression is critical for the function of all cells. The goal of this project is to better characterize a recently discovered aspect of gene regulation in which elements within mRNAs that control their translation can act in trans on other copies of the same mRNA. This phenomenon of trans regulation has the potential to explain RNA gain-of-function diseases such as myotonic dystrophy, spinocerebellar ataxia 8, Huntington's disease-like 2 and fragile X-associated tremor ataxia syndrome.